Several pieces of evidence suggest that endogenous opioids and zinc may interact to regulate neuronal excitability within the hippocampal formation. The purpose of this project was to conduct a systemic investigation into the effects of zinc on hippocampal neuronal excitability. The goal was to explain the nature of the effects of zinc and the mechanism(s) for its modulation of hippocampal excitability. It was first necessary to determine the manner in which zinc levels were to be altered, Initially, we chose to attempt to alter zinc levels by systemic administration of the intravital zinc chelators, dithizone and diethyldithiocarbamate (DEDTC). The biological assay used was the occurrence of wet dog shakes and seizures following subcutaneous administration of kainic acid (KA). Intraperitoneal injection of dithizone (12.5-100 mg/kg) or DEDTC (100-400 mg/kg) has a profound and dose related affect on the effects of KA. When given 15 minutes after subcutaneous injection of KA, they markedly potentiate KA activity. They produce a transient decrease in hippocampal levels of enkephalin and dynorphin. They also produce transient increases in the hippocampal levels of a number of amino acids (viz., taurine, glutamate, and GABA). These effects are associated with reduced levels of hippocampal zinc (as measured by Timm staining of the hippocampus). We found that DEDTC lowers the threshold for behavioral seizures elicited by electrical stimulation of the perforant path (the major input to the hippocampal formation). However, it does not lower the threshold for electrical afterdischarge. Hippocampal slices perfused with DEDTC also exhibit a lowered threshold for epileptiform bursting. This effect can be blocked by replenishing the zinc content of the tissue. These data strongly suggest that endogenous zinc plays an important role in reducing seizure activity in the hippocampus. Project was terminated January 1, 1993 due to retirement of PI.